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Structure and function of ligands for novel oxidized-LDL receptors in endothelial cell

内皮细胞中新型氧化LDL受体配体的结构和功能

基本信息

批准号：
13672317
负责人：
ADACHI Hideki
金额：
$ 2.24万
依托单位：
RIKEN(The Institute for Physical and Chemical Research)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672317/
关键词：
scavenger receptor endothelial cell oxidized LDL 動脈硬化

项目摘要

Ross's "the response-to-injury hypothesis of atherosclerosis" in the development of atherosclerosis is commonly accepted. Scavenger receptors mediate the endocytosis of chemically modified lipoproteins, such as acetylated low-density lipoprotein (Ac-LDL) and oxidized LDL (Ox-LDL), and have been implicated in the most important role for the hypothesis. The cDNAs of scavenger receptor gene family have been cloned and. its structures were deduced. LOX-1, a major receptor of oxidized LDL, SREC (scavenger receptor expressed by endothelial cell) cloned by expression cloning from human umbilical vein endothelial cells and CD36 are expressed in endothelial cells. These scavenger receptors recognize several negatively charged molecule such as modified lipoproteins and apoptic cells, and suggested for some roles in various diseases.We cloned a novel scavenger receptor termed FEEL-1 expressed in endothelial cells that was structurally unrelated to other scavenger receptors by expression cloning. The cloned receptor contained fasciclin (Fas-1), EGF-like, laminin-type EGF-like and link domains. Based on the domain structures, we temporary termed it FEEL-1 (fasciclin, EGF-like, laminin-type EGF-like and link domain-containing scavenger receptor-1). Database search suggested the presence of a paralogous gene of FEEL-1, the full-length cDNA of this gene was also cloned and its nucleotide sequence was determined. The deduced amino acid sequence of the clone indicated that its domain organization is similar to FEEL-1 and we termed this clone FEEL-2. The receptor had binding activity to cells of both Gram-positive and Gram-negative bacteria and advaned glycation end product. Moreover, in vitro tube formation assay suggested that the receptor might play a role in angiogenesis. These results suggest that FEELs play important roles in the defense mechanisms against bacterial infection, atherosclerosis and diabet.

Ross的“动脉粥样硬化损伤反应假说”在动脉粥样硬化的发展中被普遍接受。清道夫受体介导化学修饰的脂蛋白，如乙酰化低密度脂蛋白（Ac-LDL）和氧化LDL（Ox-LDL）的内吞作用，并已被牵连在最重要的作用的假说。清道夫受体基因家族的cDNA已被克隆，推测了其结构。氧化LDL的主要受体LOX-1、通过表达克隆从人脐静脉内皮细胞克隆的SREC（scavenger receptor expressed by endothelial cell）和CD 36在内皮细胞中表达。这些清道夫受体识别几种带负电荷的分子，例如修饰的脂蛋白和凋亡细胞，并暗示在各种疾病中发挥某些作用。我们通过表达克隆克隆了一种在内皮细胞中表达的新型清道夫受体FEEL-1，该受体在结构上与其他清道夫受体无关。克隆的受体包含fasciclin（Fas-1），EGF样，层粘连蛋白型EGF样和连接结构域。基于结构域的结构，我们暂时将其命名为FEEL-1（fasciclin，EGF-like，lamininin-type EGF-like and link domain-containing scavenger receptor-1）。通过数据库检索发现FEEL-1基因存在旁系同源基因，并克隆了该基因的全长cDNA，测定了其核苷酸序列。推导的氨基酸序列表明，该克隆的结构域组织类似于FEEL-1，我们将其命名为FEEL-2。该受体对革兰氏阳性菌和革兰氏阴性菌的细胞都有结合活性，并能抑制糖基化终产物。体外小管形成实验表明，该受体可能在血管生成中发挥作用。这些结果表明FEEL在抵抗细菌感染、动脉粥样硬化和糖尿病的防御机制中起重要作用。